Amodiaquine hydrochloride facilitates mycobacterial clearance via triggering autophagy in macrophages.

Abstract

OBJECTIVES: The rising prevalence of drug resistance has emerged as a major obstacle to global tuberculosis (TB) control, necessitating the development of novel host-directed strategies. This study aimed to identify compounds that enhance intracellular clearance of Mycobacterium tuberculosis (Mtb) through autophagy induction. METHODS: A cell-based screening of a G-protein-coupled receptor-related compound library was performed to identify potential autophagy inducers. Mechanistic studies were conducted in Mtb-infected macrophages to examine the effects on PI3K/AKT/mTOR signaling and ULK1 activation. In vivo efficacy was evaluated in a BALB/c mouse model of TB. RESULTS: Amodiaquine hydrochloride (CAS), a conventional antimalarial drug, was identified as a potent inducer of autophagic killing of intracellular Mtb. CAS reduced phosphorylation of PI3K, AKT, and mTOR in infected macrophages, promoting ULK1 activation and autophagy. In vivo, CAS treatment significantly decreased bacterial loads in the lungs of BALB/c mice. CONCLUSIONS: CAS represents a novel host-directed therapeutic agent that enhances intracellular clearance of Mtb by triggering autophagy in macrophages, offering a potential strategy to combat drug-resistant TB.